title: Guggulsterone attenuates activation and survival of hepatic stellate cell by inhibiting nuclear factor kappa B activation and inducing apoptosis.
abstract: OBJECTIVE
  Liver fibrosis is associated with the deposition of the extracellular matrix, and hepatic stellate cells (HSCs) are the major source of these matrix proteins. Guggulsterone has recently been shown to induce apoptosis in several cell lines. Thus, the aim of this study was to evaluate whether guggulsterone has antifibrotic activities by reducing the activation and survival of HSCs.
  
  
  METHODS
  Apoptotic and fibrosis-related signaling pathways and nuclear factor kappa B (NF-κB) activity were explored in LX-2 cells, an immortalized human HSC line, and in a mice model of liver fibrosis.
  
  
  RESULTS
  Guggulsterone suppressed LX-2 cell growth in a dose- and activation-dependent manner. This growth suppression was due to the induction of HSC apoptosis, which was mediated by the activation of c-Jun N-terminal kinase and mitochondrial apoptotic signaling. Additionally, guggulsterone regulated phosphorylation of Akt and adenosine monophosphate-activated protein kinase, which were subsequently proven responsible for the guggulsterone-induced HSC growth suppression. Guggulsterone inhibited NF-κB activation in LX-2 cells, which is one of the major mediators in HSC activation. Indeed, guggulsterone decreased collagen α1 synthesis and α-smooth muscle actin expression in these cells. Compared with the control mice or mice treated with a low dose of guggulsterone, high dose of guggulsterone significantly decreased the extent of collagen deposition and the percentage of activated HSCs undergoing apoptosis.
  
  
  CONCLUSIONS
  These results demonstrate that guggulsterone suppressed HSC activation and survival by inhibiting NF-κB activation and inducing apoptosis. Therefore, guggulsterone may be useful as an antifibrotic agent in chronic liver diseases.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; Center for Liver Cancer, National Cancer Center, Goyang, Gyeonggi-do, Korea.
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Kim
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.forename: Jong In
authors.initials: JI
authors.lastname: Yang
authors.forename: Sun Jung
authors.initials: SJ
authors.lastname: Myung
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Eun Uk
authors.initials: EU
authors.lastname: Jung
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.forename: Hyo-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Chung Yong
authors.initials: CY
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000502:physiology; D011282:Pregnenediones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013853:Thioacetamide
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D016328:NF-kappa B; D011282:Pregnenediones; D013853:Thioacetamide; D003094:Collagen; C023617:pregna-4,17-diene-3,16-dione; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: apoptosis; guggulsterone; hepatic stellate cell; liver fibrosis; nuclear factor kappa B